Abstract
Mechanisms for increased levels of quinolinic acid (QUIN) following systemic immune stimulation were investigated. In gerbils, systemic administration of pokeweed mitogen (PWM) increased plasma and cerebrospinal fluid QUIN levels, while plasma kynurenic acid levels were decreased and cerebrospinal fluid kynurenic acid levels were unchanged. PWM also increased the QUIN concentrations of brain and systemic tissues. In slices of spleen, lung, liver, duodenum, and kidney, PWM caused marked increases in [13C6]QUIN formation from L-[13C6]tryptophan (but not from [13C6]anthranilic acid). PWM also increased QUIN excretion in the urine and enhanced the formation and excretion of [13C6]QUIN following an intraperitoneal injection of L-[13C6]tryptophan. Indoleamine-2,3-dioxygenase activity was increased in the brain, kidney, lung, spleen, and duodenum while hepatic L-tryptophan-2,3-dioxygenase activity was reduced, data consistent with in vitro L-kynurenine formation from L-tryptophan. Kynurenine-3-hydroxylase activity was increased in the duodenum, lung, and spleen, but not in the brain, kidney, or liver. Kynureninase activity was increased in the brain, lung, and duodenum, but not in the spleen, kidney, or liver. 3-Hydroxyanthranilate-3,4-dioxygenase activity was unchanged in the brain, lung, and liver. No change in kynurenine aminotransferase activity was observed in the brain or lung, while liver kynurenine aminotransferase activity was reduced. We conclude that increased activities of kynurenine pathway enzymes in various tissues following systemic immune stimulation, in conjunction with macrophage infiltration of the affected tissue, provide a mechanism to account for increased concentrations of QUIN.
Highlights
Keweed mitogen(PWM)increased plasma and cerebrom- ethyl-D-aspartate receptors[8,9], a cation chelator, and an spinal fluid QUIN levels, while plasma kynurenic acid inhibitor of both hepatic phosphoenolpyruvatecarboxykinase levels were decreased and cerebrospinal fluid kynurenic acid levels were unchangePdW
Kynureninase activity was increased If accumulations of kynurenine pathway metabolites aroef in the brain, lung, adnudodenum, but not in thespleen, pathogenic significance, strategies to reduce their forkidney,orliver. 3-Hydroxyanthranilate-3,4-dioxy- mation may be of clinical benefit
Because L-KYN, anthranilicacid, and from septicemic shock, while muscle atrophy and dementia 3-hydroxyanthranilic acid can enter the brainfrom the blood may occur in patients infected with the human immunodefi- [25], induction of ~-tryptophan-2,3-dioxygenaisnethe liver, ciency virus
Summary
Studies were approved by the NIMH Animal Care and Use Committee.Female gerbils weighing 60-70 g were housedin Plexiglas cages for 5-14 days prior to study and maintained on a 12 h-12 h light-dark cycle. PWM (500pg/gerbil), ~-['~C&ryptopha(n10mg/ kg), ['3C6]anthranilic acid (10 mg/kg), and hydrocortisone 21-phosphate ( 2 5 mg/kg) were dissolved in 0.3 ml of sterile pyrogen-free salineand were administered by intraperitoneal injection via 25gauge needles. Tissue samples were collected, washed with saline, and placed in polypropylene tubes. The purpose of the present study was to characterize the effects of systemic immune stimulation on kynurenine pathway metabolism within both systemic tissues and the brain, and toinvestigate possible mechanisms for elevations in kynurenines and QUIN concentrations following immune stimulation. To accomplish these objectives, gerbils weregiven intraperitoneal injections of pokeweed mitogen (PWM, a Band T-cell stimulator) [16, 30]. The concentrations of L-KYN and['3Cs]QUIN in the medium were measured
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